An adenovirus expression vector system has been developed to deliver the cystic fibrosis transmembrane conductance regulator (CFTR) gene into the pulmonary epithelial cell's where the gene product is expressed, and where it must function in order to treat cystic fibrosis patients. Since the adenovirus vector is defective for replication and cannot persist for long periods in the epithelial cells, it will be necessary to administer the Ad-CFTR repeatedly for successful treatment. It is the long term goal of this research proposal to determine whether the Ad-CFTR vector can be used in humans to treat patients with cystic fibrosis. The specific aim of the research proposed is to determine whether the Ad-CFTR can repeatedly infect and express the CFTR gene product in the pulmonary bronchial and bronchiolar epithelial cells of the cotton rat, the animal model to be used. If sequential infections with the Ad-CFTR vector ( the vector was constructed from a type 5 adenovirus mutant) cannot be used over a long period at the intervals required to effect successful therapy, experiments will be done using other adenovirus types, since each type possesses a type-specific epitope that induces neutralizing antibodies. Using this model, it will be possible to determine whether the Ad-CFTR vector produces a pathological response, since only certain viral early gene functions are essential to produce adenovirus pneumonia.